What Causes Multiple Sclerosis (MS)?

Multiple Sclerosis (MS), the most common demyelinating disease of the central nervous system, does not have a single genetic factor as the cause unlike other central nervous system diseases where most are due to specific genetic issues.

Key takeaways:
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    Genetics although explain some risk for MS do not fully clarify the disease risk.
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    If MS is like a weapon, the gun itself is genetics, environmental factors are the bullet and the insult pulling the trigger is most likely an EBV infection.
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    One cannot modify genetically inherited risk BUT you can stop smoking, maintain a healthy weight and ensure you have a sufficient intake of Vitamin D to minimize MS risk.

The most commonly scientifically accepted hypothesis concerning the etiology of MS is that MS is an inflammatory immune-mediated disorder, characterized by autoreactive lymphocytes, that is the body’s own defenses, i.e., white blood cells, attacking the myelin sheath on the nerve cells that help speed up and shield nervous transmissions.

Genetic underpinnings

Scientific studies have shown that there are more than 200 genetic polymorphisms (variances) associated with MS. Of note, one of the strongest associations is with the certain class I and class II alleles of the major histocompatibility complex (MHC), the ubiquitous “ID Badge” proteins our cells utilize to present to our immune system the internal workings of our cells.

Interestingly, numerous HLA-DRB1 (an MHC Class 2 antigen that is associated with MS) alleles have a vitamin D response element (VDRE) in their promoter region, giving an explanation on how Vitamin D input from the environment may influence development of MS.

Family based risks

Twin studies, hallmark of demonstrating genetic risk, have shown that the risk of developing MS for dizygotic twins to be equal to that of siblings, that is 3-5% and the risk for monozygotic twins to be as low as 20 percent but as high as 40 percent.

Different studies have shown the familial MS risk to be as high as 20%. A big study done on 8200 Danish MS patients elucidated that relative lifetime risk of developing MS was seven times higher for first degree relatives, representing a 2.5% lifetime risk, compared to a .5% lifetime risk for Danish women, and .3% lifetime risk for Danish men, extremely high compared to the rest of the world.

Interestingly, data also suggest that MS risk for offspring is influenced by the sex of the affected parent, in that paternal transmission of excess MS susceptibility is higher than maternal transmission.

Environmental factors

MS is a disease of mainly northern countries. Prevalence of MS increases from south to north, and migrants from a high risk to a low-risk area carry the risk of MS over their lifetime if the migration was after puberty.

Demonstrating the possibility of sunlight exposure and Vitamin D as the causation behind this latitude effect, studies have demonstrated inverse relationships between sun exposure as well as serum Vitamin D levels and the risk of MS. Further analyses of the Nurses' Health Study and Nurses' Health Study II have elucidated that the risk of developing MS was almost halved for women taking more than 400 IU of Vitamin D daily.

Smoking, the perennial risk factor for all things health, is also associated with development of MS. Another study from Norway looking at more than 20,000 people has shown that ever-smokers had almost double the risk of developing MS as compared to never-smokers, however, other types of tobacco such as oral snuff was not associated with MS per further studies.

Obesity, the other perennial risk factor for all things health, is also a known risk factor for MS, however the exact mechanisms are yet to be elucidated.

Several scientists had hypothesized that vaccines may have a triggering role in MS, however, numerous studies did not demonstrate any associations between vaccines and MS. HPV vaccinations were not associated or indicated to increase MS risk in any studies, and most studies looking at Hepatitis B vaccinations were able to refute the link between the vaccine and MS. Of note, there was actually a negative association between tetanus vaccination and risk of MS.

MS in April babies?

A meta-analysis as well as a systematic review have shown that those born in April and May had an increased MS risk and those born in October and November had a decreased MS risk. However, the increased and decreased birth rates of those months as well as associated sunlight exposure may help these findings.

Epstein-Barr virus

Scientific literature as well as expert opinion has always suggested that there could be an infectious trigger behind MS. Epstein-Barr Virus (EBV), the causative virus behind infectious mononucleosis or mono, which has been suspected for a long time. A large study published earlier this year conducted on over 10 million US Service members, showed that more than 97% of MS cases that had never had EBV before their diagnosis, were now positive for EBV antibodies after their MS diagnosis, indicating a 32-fold increase in MS risk following an EBV infection. Although correlation never proves causation, this is as good as implicating evidence in the pathogenesis of a disease. It is most likely that EBV is the finger that pulls the trigger in those genetically and environmentally primed for MS.


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